Compositions and methods for treating macular degeneration

ABSTRACT

Methods of retarding formation of a lipofuscin pigment in the retina and of treating or ameliorating the effects of a disease characterized by an accumulation of a lipofuscin pigment in a retina are provided. These methods include the step of administering to a patient in need thereof a substituted C20-retinoid in an amount sufficient to reduce accumulation of a lipofuscin pigment in the retina. Further provided are methods of retarding formation of A2E and/or ATR-dimer by replacing an all-frans-retinal (ATR) substrate with a C20-D3-retinal substrate under conditions sufficient to impede the formation of A2E. Compositions for retarding formation of a lipofuscin pigment in the retina containing a substituted C20-retinoid and a pharmaceutically acceptable carrier are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a reissue application of U.S. Pat. No. 8,877,809,issued on Nov. 4, 2014; which is a U.S. National Stage Application ofInternational Application No. PCT/US2008/010676, which was filed on Sep.12, 2008, and which claims priority to U.S. Provisional Application No.60/993,379, which was filed on Sep. 12, 2007, all of which areincorporated by reference as if recited in full herein.

FIELD OF THE INVENTION

The present invention relates, inter alia, to compounds, compositions,and methods to slow lipofuscin formation/accumulation in order to treator ameliorate an ophthalmologic disorder, such as, e.g., maculardegeneration, without, or with reduced, adverse visual effects. Moreparticularly, the present invention relates to compounds andcompositions that may be used to treat or ameliorate an ophthalmologicdisorder, such as, e.g., macular degeneration, by slowing or limitingthe accumulation of age pigments or lipofuscin in the retinal pigmentepithelium (“RPE”) cells of the retina. The present invention alsorelates to methods of treating or ameliorating an ophthalmologicdisorder, such as, e.g., macular degeneration, in a mammal byadministering to a mammal in need of such treatment an effective amountof the compounds and/or compositions disclosed herein.

BACKGROUND OF THE INVENTION

The macula is located at the back of the eye in the center of theretina. When the millions of cells in this light-sensitive, multilayertissue deteriorate, central vision is lost along with the ability toperform tasks such as reading, writing, driving, and seeing color. This“macular degeneration” principally affects the elderly and has aprevalence of about 3% in populations between 75-79 years of age andabout 12% for populations over 80 years of age.(1) In youngerpopulations, macular degeneration is found in individuals with geneticdisorders, such as Stargardt, Vitelliform or Best (VMD), Sorsby's FundusDystrophy and Malattia Leventinese (Doyne Honeycomb or Dominant RadialDrusen). Stargardt Disease is the most common form of inherited juvenilemacular degeneration, affecting about 1 in 10,000 children.

There are no therapies currently available for genetic or dry(non-neovascular) age related macular degeneration. Vitamin supplementssuch as antioxidants, and diet changes, such as low fat diets, have beenshown to slow disease progression in some clinical studies. However, forthe majority of patients, diagnosis is followed by the progressive lossof central vision. (2-4)

The above listed macular dystrophies are all marked by the accumulationof lipofuscin, fluorescent deposits, in the retinal pigment epithelium(RPE) cell layer (5-11). The only compounds that have been characterizedto date from RPE lipofuscin, A2E (N-retinylidene-N-retinylethanolamine)and ATR-dimer (all-trans-retinal dimer), are derived from reactions ofall-trans-retinal, an isomer of 11-cis-retinal, the chromophore of thevisual pigments (12, 13). These toxic retinal dimers have been shown tocause RPE cell death, which is thought to lead to photoreceptor celldegeneration and vision loss (2, 14-22). Slowing the visual cycle usingRPE 65 antagonists (23-25) or retarding the delivery of vitamin A(retinol) to the RPE by, e.g., limiting dietary intake of vitamin A (26)or blocking serum retinol binding proteins (27) have been shown toimpede or abolish RPE lipofuscin formation in animal models. Conversely,increasing the amount of all-trans-retinal in outer segments, such asoccurs with the mutations in abcr^(−/−) (responsible for recessiveStargardt disease), leads to the rapid accumulation of lipofuscinpigments (8).

The above cited evidence leads to the conclusion that lipofuscin and/orA2E and ATR-dimer in RPE cells may reach levels that contribute to adecline in cell function followed by vision loss and that vitamin Aplays an important role in ocular lipofuscin formation.(28)

Several vitamin A analogs have been shown to limit lipofuscin formationin a mouse model by slowing down the visual cycle. The ABCR^(−/−) mousemodel has been used to test approaches to limit RPE lipofuscinformation. Mice lacking the ABCR (also known as ABCA4) gene encoding aphotoreceptor-specific adenosine triphosphate (ATP)-binding cassettetransporter, lack the ability to properly shuttle vitamin A (in the formof retinal) in the eye. ABCR^(−/−) mice were developed as an animalmodel of human recessive Stargardt's Disease (8). As in humans withrecessive Stargardt's disease, ABCR^(−/−) mice accumulate largelipofuscin deposits in RPE cells of their eyes, as shown in FIG. 1, andeventually experience delayed dark adaptation. Lipofuscin accumulationand vision loss observed in this mouse model is also thought to berelevant to age-related macular degeneration (AMD) and other maculardystrophies.

In attempts to slow down the visual cycle, visual cycle enzymes havebeen targeted. In such approaches, small molecules have been proposed asantagonists to visual cycle enzymes. In this methodology, the drug(often a vitamin A derivative) binds to visual cycle proteins, whichblocks participation by the proteins in the visual cycle, and slows thevisual cycle. Another approach to slowing the visual cycle includesimpeding the delivery of vitamin A from the blood to the eye.

Drug candidates for inhibiting lipofuscin formation by slowing down thevisual cycle have been evaluated by their ability to cause delayed darkadaptation (a side effect of an impaired visual cycle) and their abilityto impede the age related accumulation of eye lipofuscin as measured bythe concentration of A2E and other byproducts of the visual cycle, e.g.,ATR-dimer. Examples of such drug candidates and their correspondingmechanisms of action to slow the visual cycle are summarized below:

13 cis-retinoic acid (Acutane or isotretinoin) is thought to inhibit theenzymes 11-cis-retinol dehydrogenase and RPE65 involved in the visualcycle.(19, 24) When administered, 13 cis-retinoic acid has been shown tocause delayed dark adaptation. When 3-month-old ABCR knockout mice (n=3)were administered 13-cis-retinoic acid at 40 mg/kg/day for one month,the mice showed a decrease in A2E formation by about 40-50% compared tocontrol ABCR knockout mice (n=3).(24) Furthermore, when 2-month-old ABCRknockout mice were administered 13-cis-retinoic acid at 20 mg/kg/day fortwo months, the mice also showed a decrease in lipofuscin formation inthe RPE cell layer as judged by electron microscopy.

(12E,16E)-13,17,21-trimethyldocosa-12,16,20-trien-11-one (TDT) isthought to inhibit RPE65. (23) When TDT is administered to mice, delayeddark adaptation is observed. When 2-month-old ABCR knockout mice (n=2)were administered TDT at 50 mg/kg bi-weekly for two months, they showeda decrease in A2E formation by about 50-85% compared to control ABCRknockout mice (n=2).(23)

(2E,6E)-N-hexadecyl-3,7,11-trimethyldodeca-2,6,10-trienamine (TDH) isalso thought to inhibit RPE65 and when given to mice, causes delayeddark adaptation.(23) When 2-month-old ABCR knockout mice (n=2) wereadministered TDH at 50 mg/kg bi-weekly for two months, they showed adecrease in A2E formation by about 50% compared to control ABCR knockoutmice (n=2).(23)

All-trans-retinylamine (Ret-NH₂) is thought to inhibit RPE65 and whenadministered to mice results in severe delayed dark adaptation. When1-month-old ABCA4 knockout mice were given Ret-NH₂ at 40 mg/kg bi-weeklyfor two months, they showed a decrease in A2E formation by about 50%compared to control ABCA4 knockout mice.(25)

N-(4-hydroxyphenyl)retinamide (Fenretinide) slows the influx of retinolinto the eyes by reducing levels of vitamin A bound to serumretinol-binding protein. Thus, treatment with Fenretinide lowers thelevels of vitamin A in the eye which leads to delayed dark adaptation.When 2-month-old ABCA4 knockout mice (n=3) were administered Fenretinideat 20 mg/kg/day for one month, they showed a decrease in A2E formationby about 40-50% compared to control ABCA4 knockout mice (n=3).(27)

Thus, recently proposed therapeutic approaches to limit lipofuscinformation are based upon slowing the visual cycle (1, 10, 11, 12). Thereare, however, disadvantages to slowing the visual cycle as a means toimpede lipofuscin formation in order to prevent, e.g., maculardegeneration. Four of these disadvantages are detailed below.

One immediate disadvantage of slowing the visual cycle is that it leadsto delayed dark adaptation and poor vision in dim light or at night.Poor night vision (Scotopic dysfunction) is already a functional markerof early age-related maculopathy (ARM), and has been linked to theoccurrence of falls and vehicle collisions.(29, 30) A further slowingdown of the visual cycle is expected to make night vision worse inpatients who already suffer from poor night vision.

Second, in order to sufficiently impede lipofuscin formation, one wouldhave to slow down the visual cycle for a prolonged period of time. But,long-term slowing of the visual cycle leads to photoreceptor cell deathand loss of vision.(31, 32) In fact, impairment of the visual cycle isthe cause of various retinal diseases such as Stargardt's disease,retinitis pigmentosa, Lebers Congenital Amaurosis, Fundus Aibipunctatus,age-related macular degeneration and Congenital Stationary NightBlindness.

Third, the above methodology often uses vitamin A analogs to impedeproteins involved in vitamin A processing in the eye. However, vitamin Aanalogs of diverse structures, pharmacological profiles, receptoraffinities, and biologic activities have been shown to be toxic. Indeed,numerous vitamin A analogs have been shown in experimental animalmodels, cellular models, epidemiological data and clinical trials toinhibit or retard various biological functions such as, for example,bone growth, reproduction, cell division, cell differentiation andregulation of the immune system.(33-37). Thus, inhibiting vitamin Aprocessing in the eye is also expected to retard some of these basicbodily functions, which may lead to significant adverse side effects.

For example, vitamin A analogs that are currently used to treat certaincancers and/or psoriasis such as, e.g., Bexarotene (Targretin),Etretinate (Tegison) Acitretin (Soriatane), Fenretinide(N-(4-hydroxyphenyl) retinamide or 4-HPR) and 13 cis-retinoic acid(Accutane or isotretinoin) have side effects, which include, e.g., drynose, nosebleeds, chapped lips, mouth sores, increased thirst, soretongue, bleeding gums, dry mouth, cold sores, dry or irritated eyes, dryskin, peeling or scaly skin, hair loss, easy bruising, muscle aches,nausea, stomach upset, cough or swelling of the hands or feet, visionproblems, chest pain, tightness in the chest, abnormal pulse, dizziness,vomiting, severe headache, and yellowing of the eyes/skin(jaundice).(38-40)

Fourth, in animal models, candidate dugs for limiting lipofuscinformation have been shown to be effective only in relatively largedoses. For example, studies in mouse models typically use doses around11-40 mg/kg/day. But, current vitamin A analogs are typically used inthe clinic at doses of 1-3 mg/kg/day to minimize side effects. Largerdosing regimes will lead to increased side effects.

For example, Fenretinide (N-(4-hydroxyphenyl)retinamide or 4-HPR) iscurrently used to treat cancer and clinical trails are in progress forAMD. The most common adverse effects reported among 1,432 patients whounderwent treatment with this drug at a dosage of 200 mg/day for a fiveyear period were: diminished dark adaptation, cumulative incidence (16%)and dermatologic disorders (16%). Less common effects weregastrointestinal symptoms (8%) and disorders of the ocular surface(8%).(41) At this relatively low dose a delay in dark adaptation, anassessment of the effectiveness of a drug to impede lipofuscinformation, was only observed in 16% of patients. In another study whenpatients were administered larger oral doses of 600 or 900 mg/m² bid in6-week cycles, mild to moderate adverse effects were reported in 43(95%) of the 45 patients that were possibly linked to Fenretinide. Theseside effects included: fatigue, headache, skin changes (dry skin,pruritus, and rash) and digestive tract symptoms (abdominal pain,cramping, diarrhea, stomatitis, and xerostomia). Grade 2 toxicitiesreported as possibly linked to Fenretinide treatment included seizuresand confusion.(42)

A patient with an anaplastic astrocytoma who had been receivingtreatment with Fenretinide at the 600 mg/m² bid dose for one cyclepresented with headaches, nausea, and vomiting, and was found to have asmall intracranial bleed in the region of the basal ganglia. Herecovered without deficits and continued treatment without furtherevents. Another patient, who was also undergoing treatment at the 600mg/m² bid dosage and was receiving oral anticoagulation with warfarinfor deep venous thrombosis, died after developing an uncontrollablenasal bleed (international normalized ratio >6.0). Of the four patientstreated at the 900 mg/m² bid dose, one had grade 3 vomiting, grade 2speech impairment, and grade 1 memory impairment, which improved withoutresidual symptoms.(42)

A typical dose of 13 cis-retinoic acid (Accutane or isotretinoin) fortreatment of acne is 0.5 to 1 mg/kg/day for children and 2.0 mg/kg/dayfor adults for fourteen days in a row, followed by a 14-day break. Thistwenty-eight day course is usually repeated five more times.(40) Thesedoses are about 10 to 80 times less than what was used in mice to impedeA2E formation.(24) For larger doses of 13 cis-retinoic acid used totreat cancer, side effects occurring in more than 30% of users includedheadache, fever, dry skin, dry mucous membranes (mouth, nose), bonepain, nausea and vomiting, rash, mouth sores, itching, sweating, andeyesight changes.(43, 44)

Side effects occurring in 10-29% of users of 13 cis-retinoic acidinclude back pain, muscle and joint pain, allergic reaction, abdominalpain, poor appetite, dizziness, drowsiness, insomnia, anxiety, numbnessand tingling of hands and feet, weakness, depression, hair loss(thinning), dry eyes, sensitivity to light (see eye problems), decreasednight vision, which may persist after treatment is stopped, feet orankle swelling, and low blood counts.(44) In addition, it has beenobserved that white and red blood cells and platelets may temporarilydecrease, which may put a patient at increased risk for infection,anemia and/or bleeding. Side effects also include abnormal blood tests:increased triglyceride, cholesterol and/or blood sugar levels.

The above disadvantages make slowing of the visual cycle a difficultmethodology to adapt alone for the clinical treatment of ophthalmologicdisorders, e.g., macular degeneration.

SUMMARY OF THE INVENTION

Accordingly, it would be advantageous to provide treatments forophthalmologic disorders, e.g., macular degeneration, that do not have,or limit one or more of, the side effects summarized above. Inparticular, it would be advantageous to provide compounds, compositions,and methods for impeding or halting the accumulation of lipofuscin orage pigments in the RPE cells of the retina without slowing, or slowingminimally, the visual cycle.

In this regard, one embodiment of the present invention is a method ofretarding formation of a lipofuscin pigment in the retina. This methodincludes the step of administering to a patient in need thereof asubstituted C₂₀-retinoid in an amount sufficient to reduce accumulationof a lipofuscin pigment in the retina.

Another embodiment of the present invention is method of treating orameliorating the effects of a disease characterized by an accumulationof a lipofuscin pigment in a retina. This method includes the step ofadministering to a patient in need thereof a substituted C₂₀-retinoid inan amount sufficient to reduce accumulation of a lipofuscin pigment inthe retina.

A further embodiment of the present invention is a method of retardingformation of A2E. This method includes the step of replacing anall-trans-retinal (ATR) substrate with a C₂₀-D₃-retinoid substrate in apatient under conditions sufficient to impede the formation of A2E.

An additional embodiment of the present invention is a composition forretarding formation of a lipofuscin pigment in the retina containing asubstituted C₂₀-retinoid and pharmaceutically acceptable carrier.

A further embodiment of the invention is a composition comprising apharmaceutically acceptable carrier and a compound according to formulaI:

wherein:

R₁ is oxo or H;

R₂ is H or nothing;

R₃ is hydroxy or oxo or CHR₇ where R₇ forms a carotenoid and

R₄, R₅, and R₆ are independently selected from the group consisting of¹H, ²H, ³H, halogen, and C₁₋₈alkyl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows HPLC and UV-vis profiles of lipofuscin pigments extractedfrom the eyecups (six of them minus the retina) of 5.5-6 month old,ABCR^(−/−) mice. Lipofuscin pigments such A2E and ATR dimer, representedby peaks 2, 3 and 4 have been characterized and are derived fromall-trans-retinal. Other lipofuscin pigments such as peaks 1 and 5 arealso derived from all-trans-retinal, however, they have not been fullycharacterized. The above pigments are also found in humans and arethought to contribute to the macular degeneration.

FIG. 2 is a reaction scheme showing the biosynthesis of A2E andATR-dimer from all-trans-retinal and a biological amine.

FIG. 3A shows HPLC profiles of reaction mixtures ofC₂₀-D₃-all-trans-retinal and all-trans-retinal with ethanolamine for theformation of A2E. FIG. 3B is an expanded view of FIG. 3A. A2E formationwas monitored over time by measuring the appearance of peaks starting ataround 15 min. Both HPLC traces were measured about 30 hours into thereactions. For all-trans-retinal, a considerable amount of A2E hasformed as well as an unidentified compound with a retention time ataround 14.5 min as seen in the expanded view. On the other hand, forC₂₀-D₃-all-trans-retinal A2E formation is much slower and the peak at14.5 min is almost absent. FIG. 3C is a plot of A2E formation over timefor the above reactions. C₂₀-D₃-all-trans-retinal forms A2E about7-times slower than all-trans-retinal.

FIG. 4 shows HPLC profiles of reaction mixtures ofC₂₀-D₃-all-trans-retinal (A) and all-trans-retinal (B) with proline forthe formation of ATR-dimer. ATR-dimer formation was monitored over timeby measuring the appearance of peaks starting at around 8 min. Both HPLCtraces were measured about 1 hour into the reactions. Forall-trans-retinal, a considerable amount of ATR-dimer has formed. On theother hand, for C₂₀-D₃-all-trans-retinal ATR-dimer formation is muchslower. FIG. 4C is a plot of ATR-dimer formation over time for the abovereactions. C₂₀-D₃-all-trans-retinal forms A2E about 14-times slower thanall-trans-retinal.

FIG. 5 shows HPLC profiles of lipofuscin pigments extracted from theeyecups (six of them minus the retina) of 5.5-6 month old, ABCR^(−/−)mice raised on a diet of either retinol acetate (trace A (FIG. 5A)) orC₂₀-D₃-all-trans-retinol acetate (trace B (FIG. 5B)). Mice raised onretinol acetate show considerable accumulation of lipofuscin pigments asshown by the HPLC peaks. On the other hand, lipofuscin pigments wereundetectable in mice raised on the C₂₀-D₃-all-trans-retinol acetatediet. FIG. 5C shows plots of total retinol and retinol ester orD₃-retinol and D₃-retinol ester concentrations in the above mice raisedon either the retinol acetate or C₂₀-D₃-all-trans-retinol acetate diets,respectively. Both groups had roughly the same amount of retinol in theeye, despite having different concentrations of lipofuscin pigments.

FIG. 6 shows electron micrographs of RPE layers from 5.5-6 month old,ABCR^(−/−) mice raised on a diet of either retinol acetate (FIGS. 6A and6B) or C₂₀-D₃-all-trans-retinol acetate (FIGS. 6C and 6D). Due to theuncertainty in distinguishing lipofuscin from melanin bodies.Comparisons were made between the numbers of all dark, electron densebodies found in the RPE between mice on the retinol acetate diet vs.those on the C₂₀-D₃-all-trans-retinol acetate diet. In addition to theelectron dense lipofuscin and melanin bodies, RPE phagosomes,mitochondria, and lipid droplets are also present but wereultrastructurally distinct. Mice raised on the C₂₀-D₃-all-trans-retinolacetate diet have considerably less electron dense bodies (i.e.lipofuscin bodies) compared to mice raised on the retinol acetate diet.

FIG. 7A shows total A2E, as measured by HPLC peak area at 445 nm, forrats (three females per group) treated/raised on either retinal,C₂₀-D₃-retinal, retinal plus Fenretinide (FEN) or retinal plus TDH.Animals treated with retinal had the greatest amount of A2E-lipofuscin(normalized to 100%). Whereas, animals treated with C₂₀-D₃-retinal orretinal plus Fenretinide or the RPE65 antagonist, TDH, showed lessA2E-lipofuscin. FIG. 7B shows that all four groups of animals hadroughly the same amount of eye retinol. FIG. 7C shows that levels of eyeall-trans-retinal were increased in the C20-D₃-retinal group.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, methods are provided to slow lipofuscinformation that do not rely on slowing the visual cycle or smallmolecules that inhibit the visual cycle (i.e., visual cycleantagonists). Thus, many of the disadvantages, such as, delayed darkadaptation, unformed visual pigment, which can leading to visionimpairment and loss, high drug doses, and the potentially adverse sideeffects of prior methods are avoided.

More particularly, in the present invention provides methods forselectively replacing atoms on vitamin A in order to hamper itsintrinsic reactivity to form vitamin A derived lipofuscin pigments, suchas, A2E and ATR dimer, while at the same time preserving the chemicalstructure of vitamin A such that participation in the visual cycle(binding to visual cycle proteins) is minimally disturbed. Because suchchanges to the structure of vitamin A do not interfere with normalvitamin A metabolism or function, one of the utilities of the presentinvention is that many potential side effects are avoided. Furthermore,because the compounds of the present invention (disclosed in more detailbelow) do not compete with natural retinoids for protein binding(because, e.g., they can perform the job of natural retinoids), smallerdoses are needed for treatment of e.g., macular degeneration, comparedto previous treatments using, e.g., visual cycle antagonists.

In the present invention, when the C₂₀ hydrogens of all-trans-retinoidsare replaced by fluorine atoms (F₃), the formation of A2E is eliminated,as measured by monitoring the disappearance of C₂₀-F₃-all-trans-retinaland the absence of the corresponding fluorinated A2E by HPLC. A2E andthe ATR-dimer are believed to be formed in vivo by a multi-step reactionsequence involving two molecules of all-trans-retinal, as shown in FIG.2. In the first step, all-trans-retinal condenses with a biologicalamine to form the imine. This imine is then thought to undergo a [1,5]hydrogen shift involving a hydrogen atom at carbon C₂₀ (step 2).Subsequent reaction (step 3) with another molecule of retinal either by1,2- or 1,4-addition followed by cyclizations (step 4) yields A2E orATR-dimer precursors, respectively. A2E is subsequently formed afterspontaneous oxidation in air, and ATR dimer, after elimination (step 4).

It has been shown that replacing certain C—H bonds with C—F bonds inretinal (i.e., C₂₀-F₁₋₃-retinal) hampers the reactivity ofall-trans-retinal, and, thus slows or eliminates the formation of A2E invitro. By replacing hydrogen atoms at C₂₀ with fluorine, the [1,5]hydrogen shift step is blocked. Accordingly, C₂₀-F₁₋₃-retinal isexpected to appreciably slow A2E and ATR-dimer biosynthesis.

A small change in the reaction rate of all-trans-retinal to form itstoxic dimers is expected to translate into a large decrease in RPElipofuscin formation over a lifetime. The methods of the presentinvention will slow the formation of the toxic pigments and will notslow (or will not slow significantly) visual cycle kinetics, because theregeneration of 11-cis-retinal does not involve the breaking of the C₂₀hydrogen bond. Therefore, treatment with a C₂₀-F₁₋₃-retinoid (which maybe transformed into C₂₀-F₁₋₃-retinal in the body) will be particularlyuseful in impeding lipofuscin formation in humans who suffer fromStargardt Disease or other diseases or conditions associated withlipofuscin formation and/or macular degenerations.

C₂₀-D₁₋₃-retinoid according to the present invention will also be usefulas a therapy to treat or ameliorate macular degeneration without adverse(or significantly adverse) visual effects. When C₂₀ hydrogens arereplaced by deuteriums, A2E formation is about seven times slower (FIG.3) and ATR-dimer formation is about 15 times slower (FIG. 4). Thiskinetic isotope effect will slow A2E and ATR-dimer formation in vivo.Deuterated vitamin A is widely used in humans and shows no toxicity (45,46). Thus, a treatment using a C₂₀-D₁₋₃-retinoid should be an effectiveand non-toxic therapy to treat or ameliorate macular degenerationwithout adverse visual effects.

In view of the foregoing, one embodiment of the present invention is amethod of retarding formation of a lipofuscin pigment in the retina.This method includes the step of administering to a patient in needthereof a substituted C₂₀-retinoid in an amount sufficient to reduceaccumulation of a lipofuscin pigment in the retina. Preferably, thesubstituted C₂₀-retinoid is selected from the group consisting of aC₂₀-D₁₋₃-retinoid and a C₂₀-F₁₋₃-retinoid. Preferably, the lipofuscinpigment is selected from the group consisting of A2E, all-trans-retinoid(ATR)-dimer, and combinations thereof.

Preferably, the substituted C₂₀-retinoid is administered to the patientas part of a pharmaceutical or a nutraceutical composition. Preferably,the substituted C₂₀-retinoid is administered as a unit dosage form.

In the present invention, the patient may be a mammal, preferably ahuman. In this embodiment, the substituted C₂₀-retinoid is a compound orcombination of compounds disclosed herein, preferably compounds ofFormula I, including Formulae Ic-Ie and Formula II, which are definedbelow.

In this embodiment, an amount sufficient to reduce accumulation of alipofuscin pigment in the retina will vary by patient and the particularsubstituted C₂₀-retinoid used. Typically, such amount will be about 0.05to about 300 mg/day, including, e.g., 0.5-50, 1-25, and 3-10 mg/day.

Another embodiment of the present invention is method of treating orameliorating the effects of an ophthalmologic disorder, such as, e.g. adisease characterized by an accumulation of a lipofuscin pigment in aretina. This method includes the step of administering to a patient inneed thereof a substituted C₂₀-retinoid in an amount sufficient toreduce accumulation of a lipofuscin pigment in the retina. Preferably,the substituted C₂₀-retinoid is selected from the group consisting ofC₂₀-D₁₋₃-retinoids and C₂₀-F₁₋₃-retinoids. Preferably, the lipofuscinpigment is selected from the group consisting of A2E, ATR-dimer, andcombinations thereof.

Preferably, the substituted C₂₀-retinoid is administered as part of apharmaceutical or a nutraceutical composition. Preferably, thesubstituted C₂₀-retinoid is administered as a unit dosage form.

In this embodiment, the disease maybe selected from the group consistingof Stargardt, Vitelliform or Best (VMD), Sorsby's Fundus Dystrophy, agerelated macular degeneration, and Malattia Leventinese. Preferably, thedisease is macular degeneration.

In this embodiment, the administration step includes replacing acomponent of the patient's diet that contains retinoid(s) or Vitamin Awith a component that contains a substituted C₂₀-retinoid. By “replacinga component of a patient's diet” it is meant that a part of the dietthat contains vitamin A or its precursors (including, but not limited tocarotenoids) is replaced with a component that contains a substitutedC₂₀-retinoid. Preferably, from about 1% to about 95%, including, e.g.,from about 5-75%, 10-50%, or 20-30%, of the retinoid(s) in the patient'sdiet is replaced with a substituted C₂₀-retinoid. The replacement may bethrough, e.g., administering substituted C₂₀-retinoid containing foodsor through treatment with compositions of the present invention,including pharmaceuticals or nutraceuticals, in lieu of consumingretinoid- or Vitamin A-containing foods that would have otherwise beenconsumed.

An additional embodiment of the present invention is a composition forretarding formation of a lipofuscin pigment in the retina, whichcomposition contains a substituted C₂₀-retinoid and a pharmaceuticallyacceptable carrier. Preferably, the substituted C₂₀-retinoid is selectedfrom the group consisting of C₂₀-D₁₋₃-retinoid and C₂₀-F₁₋₃-retinoid.Preferably, the composition is in a unit dosage form. Preferably, thecomposition is a vitamin supplement or a pharmaceutical formulation.

A further embodiment of the present invention is a method of retardingformation of a lipofuscin pigment selected from the group consisting ofan A2E, an ATR dimer, and combinations thereof. This method comprisesreplacing an all-trans-retinal (ATR) substrate with a C₂₀-D₃-retinoidsubstrate under conditions sufficient to impede the formation of A2E,ATR dimer, or both, or an A2E and/or an ATR-dimer derivative. As used inthe present invention, “conditions sufficient to impede the formation ofA2E, ATR dimer, or both are well known in the art or may be determinedempirically, if desired. The replacing step in this embodiment isdescribed in more detail below.

A further embodiment of the present invention is a method of retardingformation of A2E. This method includes the step of replacing anall-trans-retinal (ATR) substrate with a C₂₀-D₃-retinoid substrate underconditions sufficient to impede the formation of A2E. The replacing stepin the last two embodiments may be accomplished using known method,including the methods disclosed above. For example, the substratereplacement may take place in the eye of the patient, e.g., thesubstrate may be administered directly to the eye via eye drops,ointment, or injection. Alternatively, the substrate may be administeredsystemically via, e.g., ingestion of a pill or capsule or absorptionthrough a patch or by injection.

In the present invention, the “substituted C₂₀-retinoid” includes allretinols, retinol acetates, retinol esters, and retinoic acids asdefined below as well as pharmaceutical salts thereof and metabolitesthereof. For purposes of the present invention, the number scheme setforth in formula Ia for retinoids shall be used:

Thus, retinol, retinol acetate, retinol palmitate, retinoic acid, andbeta-carotene have the following structures:

wherein

-   R₁ and R₂ are both H and R₃ is OH (retinol); or-   R₁ and R₂ are both H and R₃ is OCOCH₃ (retinol acetate); or-   R₁ and R₂ are both H and R₃ is OCOR (retinol ester such as, e.g.,    retinol palmitate) or-   R₁ is ═O, R₂ is nothing and R₃ is OH (retinoic acid) or-   R₁ is H, R₃ is nothing, and R₂ is ═CH—R₇, where R₇ forms a    carotenoid. In this embodiment, R₇ together with the rest of the    compound forms, e.g., a beta-carotene or another pro-vitamin A    carotenoid such as the deuterated beta-carotene shown in formulae    Ib′ below:

Exemplary substituted C₂₀-retinoid compounds that may be used in thecompositions of the present invention include the following (compoundsIc-Ie):

wherein R₁, R₂, and R₃ are as defined in Formula Ib.

Exemplary methods and reaction schemes for making substitutedC20-retinoid compounds according to the present invention are set forthbelow:

In another embodiment, the invention is a composition comprising apharmaceutically acceptable carrier and a compound according to formulaI:

wherein:

R₁ is oxo or H;

R₂ is H or nothing;

R₃ is hydroxy or oxo or ═CH—R₇, where R₇ forms a carotenoid; and R₄, R₅,and R₆ are independently selected from the group consisting of ²H (D),³H (T), halogen, and C₁₋₈alkyl. Preferably, the halogen is fluorine (F).

In this embodiment, R₄, R₅, and R₆ may also be independently selectedfrom H or a substituent that slows lipofuscin formation, a substituentthat slows the formation of at least one of A2E or ATR dimer formation,or a substituent that slows hydrogen abstraction or migration at the C₂₀position compared to a retinoid that is not substituted at the C₂₀position, e.g. a C₂₀—H₃ retinoid. The present invention furthercontemplates any combination of the foregoing substituents at R₄, R₅,and R₆.

Preferably, in the composition of the present invention the compound hasthe structure of formula II:

wherein:

R₁ is oxo or H;

R₂ is H or nothing; and

R₃ is hydroxy or oxo or ═CH—R₇, where R₇ forms a carotenoid.

In the present invention, the compositions may further contain asupplement. Representative, non-limiting examples of a supplementaccording to the present invention are visual cycle antagonists,molecules that inhibit influx of a retinoid into an eye, or combinationsthereof.

Exemplary, non-limiting visual cycle antagonists according to thepresent invention include TDH, TDT, 13-cis-retinoic acid, ret-NH₂, andcombinations thereof. An exemplary, non-limiting visual cycle antagonistaccording to the present invention is fenretinide. Other visual cycleantagonists within the scope of the present invention include thosedisclosed in R. Rando, U.S. application Ser. No. 11/199,594 filed Aug.8, 2005, which application is incorporated by reference as if recited infull herein.

In the present invention, one or more additives may be included in thecompositions. Exemplary, non-limiting additives that may be included inthe compositions of the present invention include zinc, vitamin E,vitamin D, and combinations thereof.

The zinc, vitamin E, and vitamin D additives may be present in thecompositions of the present invention in amounts that are effective to,e.g., enhance the bioavailability of the substituted C₂₀-retinoidcompounds of the present invention, including Formula I, Formulae Ic-e,and Formula II. Thus, in the present invention, zinc may be present inthe composition at between about 3 to about 80 mg, preferably betweenabout 3 to about 10 mg or between about 10 to about 80 mg. Vitamin E maybe present in the composition at between about 3 to about 3,000 mg,preferably between about 3 to about 15 mg or between about 15 to about3,000 mg. Vitamin D may be present in the composition at between about0.005 to about 0.1 mg, preferably between about 0.005 to about 0.015 mgor between about 0.015 to about 0.1 mg.

The compositions of the present invention may also include one or moreadditional additives, including, for example, eye antioxidants,minerals, negatively-charged phospholipids, carotenoids, andcombinations thereof. The use of anti-oxidants has been shown to benefitpatients with macular degenerations and dystrophies. See, e.g., Arch.Ophthalmol., 119: 1417-36 (2001); Sparrow, et al., J. Biol. Chem.,278:18207-13 (2003). Examples of suitable anti-oxidants that could beused in a composition of the present invention in combination with acompound of formulae I, including formulae Ic-le and II, include vitaminC, vitamin E, beta-carotene and other carotenoids, coenzyme Q, OT-551(Othera Pharmaceuticals Inc.),4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol),butylated hydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E),bilberry extract, and combinations thereof.

The use of certain minerals has also been shown to benefit patients withmacular degenerations and dystrophies. See, e.g., Arch. Ophthalmol.,119: 1417-36 (2001). Thus, the present invention contemplates theoptional inclusion of one or more of such minerals. Examples of suitableminerals that could be used in a composition of the present inventioninclude copper-containing minerals, such as cupric oxide (by way ofexample only); zinc-containing minerals, such as zinc oxide (by way ofexample only); and selenium-containing compounds, and combinationsthereof.

The use of certain negatively-charged phospholipids has also been shownto benefit patients with macular degenerations and dystrophies. See,e.g., Shaban & Richter, Biol. Chem., 383:537-45 (2002); Shaban, et al.,Exp. Eye Res., 75:99-108 (2002). Examples of suitable negatively chargedphospholipids that could optionally be used in a composition of thepresent invention include cardiolipin, phosphatidylglycerol, andcombinations thereof. Positively-charged and/or neutral phospholipidsmay also provide benefit for patients with macular degenerations anddystrophies when used in combination with a composition of the presentinvention.

The use of certain carotenoids has been correlated with the maintenanceof photoprotection necessary in photoreceptor cells. Carotenoids arenaturally-occurring yellow to red pigments of the terpenoid group thatcan be found in plants, algae, bacteria, and certain animals, such asbirds and shell-fish. Carotenoids are a large class of molecules inwhich more than 600 naturally occurring carotenoids have beenidentified. Carotenoids include hydrocarbons (carotenes) and theiroxygenated, alcoholic derivatives (xanthophylls). They includeactinioerythrol, astaxanthin, canthaxanthin, capsanthin, capsorubin,beta-8′-apo-carotenal (apo-carotenal), beta-12′-apo-carotenal,alpha-carotene, beta-carotene, “carotene” (a mixture of alpha- andbeta-carotenes), gamma-carotenes, beta-cyrptoxanthin, lutein, lycopene,violerythrin, zeaxanthin, and esters of hydroxyl- or carboxyl-containingmembers thereof. Many of the carotenoids occur in nature as cis- andtrans-isomeric forms, while synthetic compounds are frequently racemicmixtures.

In humans, the retina selectively accumulates mainly two carotenoids:zeaxanthin and lutein. These two carotenoids are thought to aid inprotecting the retina because they are powerful antioxidants and absorbblue light. Examples of suitable carotenoids for optional use in acomposition of the present invention include lutein and zeaxanthin, aswell as any of the aforementioned carotenoids and combinations thereof.

Effective dosage forms, modes of administration, and dosage amounts, inaddition to those disclosed above, may be determined empirically, andmaking such determinations is within the skill of the art. It isunderstood by those skilled in the art that the dosage amount will varywith the route of administration, the rate of excretion, the duration ofthe treatment, the identity of any other drugs being administered, theage, size, and species of mammal, e.g., human patient, and like factorswell known in the arts of medicine and veterinary medicine. In general,a suitable dose of a compound according to the invention will be thatamount of the compound, which is the lowest dose effective to producethe desired effect. For example, a compound of the invention is presentin the composition at a level sufficient to deliver about 0.1 to about90 mg/day to a patient. The effective dose of a compound maybeadministered as two, three, four, five, six or more sub-doses,administered separately at appropriate intervals throughout the day.

A compound of the present invention may be administered in any desiredand effective manner: as pharmaceutical compositions for oral ingestion,or as an ointment or drop for local administration to the eyes, or forparenteral or other administration in any appropriate manner such asintraperitoneal, subcutaneous, topical, intradermal, inhalation,intrapulmonary, rectal, vaginal, sublingual, intramuscular, intravenous,intraarterial, intrathecal, or intralymphatic. Further, a compound ofthe present invention may be administered in conjunction with othertreatments. A compound or composition of the present invention maybeencapsulated or otherwise protected against gastric or other secretions,if desired.

While it is possible for a compound of the invention to be administeredalone, it is preferable to administer the compound as a pharmaceuticalformulation (composition) or a vitamin supplement or a nutraceutical.The pharmaceutically acceptable compositions of the invention compriseone or more compounds as an active ingredient in admixture with one ormore pharmaceutically-acceptable carriers and, optionally, one or moreother compounds, drugs, ingredients and/or materials. Regardless of theroute of administration selected, the compounds of the present inventionare formulated into pharmaceutically-acceptable dosage forms byconventional methods known to those of skill in the art. See, e.g.,Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).

Pharmaceutically acceptable carriers are well known in the art (see,e.g., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton,Pa.) and The National Formulary (American Pharmaceutical Association,Washington, D.C.)) and include sugars (e.g., lactose, sucrose, mannitol,and sorbitol), starches, cellulose preparations, calcium phosphates(e.g., dicalcium phosphate, tricalcium phosphate and calcium hydrogenphosphate), sodium citrate, water, aqueous solutions (e.g., saline,sodium chloride injection, Ringer's injection, dextrose injection,dextrose and sodium chloride injection, lactated Ringer's injection),alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol),polyols (e.g., glycerol, propylene glycol, and polyethylene glycol),organic esters (e.g., ethyl oleate and tryglycerides), biodegradablepolymers (e.g., polylactide-polyglycolide, poly(orthoesters), andpoly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils(e.g., corn, germ, olive, castor, sesame, cottonseed, and groundnut),cocoa butter, waxes (e.g., suppository waxes), paraffins, silicones,talc, silicylate, etc. Each pharmaceutically acceptable carrier used ina pharmaceutical composition of the invention must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not injurious to the subject. Carriers suitable for aselected dosage form and intended route of administration are well knownin the art, and acceptable carriers for a chosen dosage form and methodof administration can be determined using ordinary skill in the art.

The pharmaceutical compositions or vitamin supplements or nutraceuticalsof the invention may, optionally, contain additional ingredients and/ormaterials commonly used in such pharmaceutical compositions or vitaminsupplements or nutraceuticals. These ingredients and materials are wellknown in the art and include (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, suchas carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, suchas glycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,sodium starch glycolate, cross-linked sodium carboxymethyl cellulose andsodium carbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as cetyl alcohol and glycerol monosterate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,and sodium lauryl sulfate; (10) suspending agents, such as ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth; (11) buffering agents; (12) excipients, such as lactose,milk sugars, polyethylene glycols, animal and vegetable fats, oils,waxes, paraffins, cocoa butter, starches, tragacanth, cellulosederivatives, polyethylene glycol, silicones, bentonites, silicic acid,talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, andpolyamide powder; (13) inert diluents, such as water or other solvents;(14) preservatives; (15) surface-active agents; (16) dispersing agents;(17) control-release or absorption-delaying agents, such ashydroxypropylmethyl cellulose, other polymer matrices, biodegradablepolymers, liposomes, microspheres, aluminum monosterate, gelatin, andwaxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21)emulsifying and suspending agents; (22), solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan; (23)propellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane; (24) antioxidants; (25) agentswhich render the formulation isotonic with the blood of the intendedrecipient, such as sugars and sodium chloride; (26) thickening agents;(27) coating materials, such as lecithin; and (28) sweetening,flavoring, coloring, perfuming and preservative agents. Each suchingredient or material must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Ingredients and materials suitable for aselected dosage form and intended route of administration are well knownin the art, and acceptable ingredients and materials for a chosen dosageform and method of administration may be determined using ordinary skillin the art.

Pharmaceutical compositions or vitamin supplements or nutraceuticalssuitable for oral administration may be in the form of capsules,cachets, pills, tablets, powders, granules, a solution or a suspensionin an aqueous or non-aqueous liquid, an oil-in-water or water-in-oilliquid emulsion, an elixir or syrup, a pastille, a bolus, an electuaryor a paste. These formulations may be prepared by methods known in theart, e.g., by means of conventional pan-coating, mixing, granulation orlyophilization processes.

Solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like) may be prepared by mixing theactive ingredient(s) with one or more pharmaceutically-acceptablecarriers and, optionally, one or more fillers, extenders, binders,humectants, disintegrating agents, solution retarding agents, absorptionaccelerators, wetting agents, absorbents, lubricants, and/or coloringagents. Solid compositions of a similar type maybe employed as fillersin soft and hard-filled gelatin capsules using a suitable excipient. Atablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared using asuitable binder, lubricant, inert diluent, preservative, disintegrant,surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine. The tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.They may also be formulated so as to provide slow or controlled releaseof the active ingredient therein. They may be sterilized by, forexample, filtration through a bacteria-retaining filter. Thesecompositions may also optionally contain opacifying agents and may be ofa composition such that they release the active ingredient only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. The active ingredient can also be inmicroencapsulated form.

Liquid dosage forms for oral administration includepharmaceutically-acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. The liquid dosage forms may containsuitable inert diluents commonly used in the art. Besides inertdiluents, the oral compositions may also include adjuvants, such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents. Suspensions maycontain suspending agents.

Pharmaceutical compositions for rectal or vaginal administration may bepresented as a suppository, which maybe prepared by mixing one or moreactive ingredient(s) with one or more suitable nonirritating carrierswhich are solid at room temperature, but liquid at body temperature and,therefore, will melt in the rectum or vaginal cavity and release theactive compound. Pharmaceutical compositions which are suitable forvaginal administration also include pessaries, tampons, creams, gels,pastes, foams or spray formulations containing suchpharmaceutically-acceptable carriers as are known in the art to beappropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches, drops and inhalants. The active compound may be mixed understerile conditions with a suitable pharmaceutically-acceptable carrier.The ointments, pastes, creams and gels may contain excipients. Powdersand sprays may contain excipients and propellants.

Pharmaceutical compositions suitable for parenteral administrationscomprise one or more compound in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain suitable antioxidants,buffers, solutes which render the formulation isotonic with the blood ofthe intended recipient, or suspending or thickening agents. Properfluidity can be maintained, for example, by the use of coatingmaterials, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants. These compositions mayalso contain suitable adjuvants, such as wetting agents, emulsifyingagents and dispersing agents. It may also be desirable to includeisotonic agents. In addition, prolonged absorption of the injectablepharmaceutical form may be brought about by the inclusion of agentswhich delay absorption.

In some cases, in order to prolong the effect of a drug (e.g.,pharmaceutical formulation or vitamin supplement or nutraceutical), itis desirable to slow its absorption from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility.

The rate of absorption of the drug then depends upon its rate ofdissolution which, in turn, may depend upon crystal size and crystallineform. Alternatively, delayed absorption of a parenterally-administereddrug may be accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms may be made by forming microencapsulematrices of the active ingredient in biodegradable polymers. Dependingon the ratio of the active ingredient to polymer, and the nature of theparticular polymer employed, the rate of active ingredient release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissue. The injectable materials can be sterilized forexample, by filtration through a bacterial-retaining filter.

The formulations may be presented in unit-dose or multi-dose sealedcontainers, for example, ampules and vials, and may be stored in alyophilized condition requiring only the addition of the sterile liquidcarrier, for example water for injection, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the type described above.

The following examples are provided to further illustrate the methods ofthe present invention. These examples are illustrative only and are notintended to limit the scope of the invention in any way.

EXAMPLES Example 1 Replacing the C₂₀ Hydrogens of all-Trans-Retinal withDeuteriums Slows the Formation of A2E In Vitro

C₂₀-D₃-retinal was prepared according to the literature procedure (47)and its in vitro ability to form A2E as compared to all-trans-retinalwas measured by HPLC.

FIG. 3A plots the formation of all A2E for two reaction mixturescontaining either all-trans-retinal or C₂₀-D₃-all-trans-retinal (16 mg),ethanolamine (0.5 equivalents) and acetic acid (1.2 equivalents). Atypical HPLC trace is shown in FIG. 3B for the all-trans-retinal andC₂₀-D₃-all-trans-retinal reaction mixtures. The area under the curvecorresponds to the amount of A2E: the larger the area the more A2E. Theconcentrations of A2E in the two reactions mixtures were measured aboutevery 8 hours for 50 hours. The concentrations at each time point wasplotted and the data points fit to a line for each reaction mixture. Acomparison of the slopes of the two lines for the two reaction revealedthat A2E formation occurred 7-times faster for all-trans-retinalcompared to C₂₀-D₃-all-trans-retinal. Hydrogen deuterium exchange wasnot observed during the reaction with the labeled retinal, as measuredby mass spectrometry of the reaction mixture after 50 hours, whichclearly showed the presence of the tri-deuterated retinal,tri-deuterated retinal hydroxylamine Schiff base and tetra-deuteratedA2E.

Example 2 Replacing the C₂₀ Hydrogens of All-Trans-Retinal withDeuteriums Slows the Formation of ATR-Dimer In Vitro

C₂₀-D₃-all-trans-retinal was prepared as described in Example 1 and itsin vitro ability to form ATR-dimer as compared to all-trans-retinal wasmeasured by HPLC. All-trans-retinal or C₂₀-D₃-all-trans-retinal (10 mg)and proline (2 equivalents) in ethanol were mixed, and the reaction wasfollowed by HPLC, the results of which are depicted in FIG. 4A. Atypical HPLC trace is shown in FIG. 4B for the all-trans-retinal andC₂₀-D₃-all-trans-retinal reaction mixtures at the same time points. Theconcentrations of ATR-dimer in the two reaction mixtures were measuredabout every 15 min for 3 hours. The concentration at each time point wasplotted and the data points fit to a line for each reaction mixture. Acomparison of the slopes of the two lines showed thatC₂₀-D₃-all-trans-retinal formed ATR-dimer 15 times slower than theunlabeled retinal as shown in FIG. 4C.

Example 3 Replacing the C₂₀ Hydrogens of All-Trans-Retinal withDeuteriums Slows the Formation of A2E-Lipofuscin in CD-1 (ICR) Mice

C₂₀-D₃-all-trans-retinal was administered to mice in order to measureits ability to form A2E in the eye compared to all-trans-retinal. Nine,8-week old, CD-1 (ICR) mice (from Charles River, Wilmington, Mass.) weredivided up into two groups of five and administered 1.5 mg of etherall-trans-retinal or C₂₀-D₃-all-trans-retinal by intraperitonealinjection (IP) injection in a 10% solution of Tween-20 in salinebi-weekly for 6 weeks. At the end of this six-week period, each mousewas given a total of 60,000 I.U.(18 mg) or about 28-times the originalamount of vitamin A in the mouse's body. Massive dosing withC₂₀-D₃-all-trans-retinal quickly replaces normal vitamin A stores withthe C₂₀-D₃-analog. And, the injected retinal rapidly accumulates in theeye (rod outer segments), where at high enough concentrations it willreact to form lipofuscin pigments. This is similar to the accumulationof all-trans-retinal in the ABCR^(−/−) mice and in patents withStargardt's disease.

At the end of the six week period, the eyes were dissected, the retinasand eyecups pooled into groups of 4 or 5, and homogenated with 50 μLethanol. The homogenate was centrifuged at 13,000 rpm for 5 minutes and40 μL of the supernatant was drawn off and analyzed for A2E-lipofuscinby HPLC. Retinol and retinol esters were analyzed at 325 nm andA2E-lipofuscin was measured at 445 nm. Mice administeredC₂₀-D₃-all-trans-retinal (n=5) had 68% less A2E-lipofuscin as comparedto mice administered all-trans-retinal (n=4). Both groups of mice hadroughly the same concentrations of retinol and retinol esters.

Example 4 Replacing the C₂₀ Hydrogens of All-Trans-Retinal withDeuteriums Reduces the Formation of A2E in ABCR^(−/−) Mice

C₂₀-D₃-all-trans-retinol acetate was prepared according to theliterature procedure (47) and was administered to ABCR^(−/−) mice (48,49) in order to measure its ability to lead to lipofuscin compared tothat of all-trans-retinol acetate. Eight 2-month old, ABCR^(−/−) miceraised on a standard rodent diet were then fed a diet containing 20,000I.U./kg of either C₂₀-D₃-all-trans-retinol acetate or all-trans-retinolacetate for 3 months. On this diet each mouse roughly received thedaily-recommended amount of vitamin A or the same amount of theC₂₀-D₃-vitamin A drug, which was less than about 1 mg/kg/day.

At the end of the 5 month period, the eyes were dissected, eyecupspooled into groups of six and homogenated with 80 μL ethanol. Thehomogenate was centrifuged at 13000 rpm for 5 min and 30 μL of thesupernatant was drawn off and analyzed for A2E-lipofuscin by HPLC.A2E-lipofuscin was measured at 445 nm. Mice on the 3-month dietcontaining C₂₀-D₃-all-trans-retinol acetate had 44-58% lessA2E-lipofuscin as compared to mice on a diet of all-trans-retinolacetate. This percentage of A2E reduction is on the same order ofmagnitude observed in similar studies in ABCR^(−/−) mice with the visualcycle antagonist TDH, TDT, Ret-NH₂, 13-cis-retinoic, acid andfenretinide. However, in this example A2E reduction is achieved withdoses of C₂₀-D₃-all-trans-retinol acetate that are 11- to 40-times less.

Example 5 ABCR^(−/−) Mice Raised Exclusively on aC₂₀-D₃-All-Trans-Retinol Acetate Diet Show Undetectable Amounts ofExtractable Lipofuscin Pigments and Reduced Lipofuscin Deposits

As in Example 4, two groups of four ABCR^(−/−) mice where raised eitheron diets containing C₂₀-D₃-all-trans-retinol acetate orall-trans-retinol acetate. However, in this example the mice wereoffspring of mothers on the same diet, and thus where raised only ontheir respective vitamin A analogs. At 5.5-6 months of age the mice weresacrificed and the eyecups were analyzed for lipofuscin pigments asdescribed in Example 4. The results are shown FIG. 5. While both micecontained the same amount of eye retinol and retinol esters (FIG. 5C)lipofuscin pigments were undetectable in mice raised on theC₂₀-D₃-all-trans-retinol acetate diet (FIG. 5B) but were detectable inmice raised on the all-trans-retinol acetate diet (FIG. 5A).

In order to measure the amount lipofuscin granules in the eyes of theabove mice on a normal diet vs. the diet containingC20D₃-all-trans-retinol acetate, eyecups from both groups of mice (2from each group) were evaluated by electron microscopy. Mice on theC₂₀-D₃-all-trans-retinol acetate diet had less electron dense lipofuscindeposits compared to mice on a diet of all-trans-retinol acetate asshown in FIG. 6.

Example 6 C₂₀-D₃-All-Trans-Retinal Slows A2E-Lipofuscin Formation asWell as Fenretinide and/or TDH in Wild-Type Rats

45-50 day old, female, CD IGS rats (Charles River, Wilmington, Mass.)were divided up into four groups of three. Three of these groups wereadministered all-trans-retinal and the one group was givenC₂₀-D₃-all-trans-retinal (IP injection in a 10% solution of Tween-20 insaline) at 3 mg, bi- or tri-weekly for 8 weeks (20, 3 mg injectionstotal). Thus, at the end of the 8-week period the animals receivedroughly 20 times their original stores of vitamin A, as retinal orC₂₀-D₃-all-trans-retinal. Massive dosing with C₂₀-D₃-all-trans-retinalquickly replaces normal vitamin A stores with the C₂₀-D₃₋analog. Of thethree groups administered all-trans-retinal, one group was givenFenretinide (50) and another TDH (23), at doses of roughly 1.5mg/day/animal (both supplied in the drinking water emulsified with 1 g/Lof Nu-rice (RIBUS, Inc, St. Louis, Mo.)).

At the end of the 8 weeks, RPE, A2E-lipofuscin was evaluated in each ofthe four groups by HPLC as described in Example 3 and in FIG. 7.A2E-lipofuscin pigments were greatest in the animals receivingall-trans-retinal (the control group). While animals receivingC₂₀D₃-all-trans-retinal had 35% less A2E-lipofuscin than animalsreceiving all-trans-retinal. Likewise, animals receiving Fenretinide orTDH had 49% and 31% less A2E-lipofuscin compared to animals administeredonly all-trans-retinal.

CITED DOCUMENTS

The following documents, which have been cited above, are incorporatedby reference as if recited in full herein:

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The scope of the present invention is not limited by the description,examples, and suggested uses herein and modifications can be madewithout departing from the spirit of the invention. Thus, it is intendedthat the present invention cover modifications and variations of thisinvention provided that they come within the scope of the appendedclaims and their equivalents.

What is claimed is:
 1. A method of retarding the accumulation of alipofuscin pigment in a retina, comprising administering an effectiveamount of a pharmaceutical composition to a patient in need thereof,wherein the pharmaceutical composition comprises a substitutedC₂₀-D₁₋₃-retinoid, wherein the C₂₀-D₁₋₃-retinoid is selected from thegroup consisting of C₂₀-D₁₋₃-retinol, C₂₀-D₁₋₃-retinol ester,C₂₀-D₁₋₃-retinal, and C₂₀-D₁₋₃-pro-vitamin A carotenoids, and apharmaceutically acceptable carrier.
 2. The method according to claim 1,wherein the substituted C₂₀-D₁₋₃-retinoid is a C₂₀-D₃-retinoid.
 3. Themethod according to claim 1, wherein the pharmaceutical composition issuitable for use as a nutraceutical composition.
 4. The method accordingto claim 1, wherein the patient is in need of treatment for a maculardegeneration.
 5. The method according to claim 4, wherein the maculardegeneration is age-related macular degeneration.
 6. The methodaccording to claim 5, wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₁₋₃-retinolor a C₂₀-D₁₋₃-retinol ester.
 7. The method according to claim 5, whereinthe C₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinol, a C₂₀-D₃-retinol ester,C₂₀-D₃-retinal, or a C₂₀-D₃-pro-vitamin A carotenoid.
 8. The methodaccording to claim 5, wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinolacetate.
 9. The method according to claim 8, wherein the C₂₀-D₃-retinal,corresponding to the aldehyde of the C₂₀-D₃-retinol acetate, forms A2Ein vitro about 7 times slower than non-deuterium-enriched retinalretinol acetate.
 10. The method according to claim 5, wherein thepatient is in need of treatment for dry (non-neovascular) age-relatedmacular degeneration.
 11. The method according to claim 1, wherein thepatient is in need of treatment for Stargardt disease.
 12. The methodaccording to claim 11, wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₁₋₃-retinolor a C₂₀-D₁₋₃-retinol ester.
 13. The method according to claim 11,wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinol, a C₂₀-D₃-retinol ester,C₂₀-D₃-retinal, or a C₂₀-D₃-pro-vitamin A-carotenoid.
 14. The methodaccording to claim 11, wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinolacetate.
 15. The method according to claim 14, wherein theC₂₀-D₃-retinal, corresponding to the aldehyde of the C₂₀-D₃-retinolacetate, forms A2E in vitro about 7 times slower thannon-deuterium-enriched retinal retinol acetate.
 16. The method accordingto claim 1, wherein the patient is in need of treatment for a maculardegeneration selected from the group consisting of Vitelliform or Bestdisease, Sorsby's fundus dystrophy, retinitis pigmentosa, and MalattiaLeventinese.
 17. The method according to claim 16, wherein theC₂₀-D₁₋₃-retinoid is C₂O-D₃-retinol C₂₀-D₃-retinol acetate.
 18. Themethod according to claim 1, wherein the patient is in need of treatmentfor a macular degeneration characterized by one or more mutation(s) inthe ABCA4 gene.
 19. The method according to claim 1, wherein thesubstituted C₂₀-D₁₋₃-retinoid is present in the pharmaceuticalcomposition at a level sufficient to deliver on average about 0.1 toabout 90 mg/day to a patient.
 20. The method according to claim 1,further comprising an additional active.
 21. The method according toclaim 20, wherein the additional active is selected from the groupconsisting of eye antioxidants, minerals, negatively-chargedphospholipids, carotenoids, and combinations thereof.
 22. The methodaccording to claim 21, wherein the eye antioxidant is selected from thegroup consisting of vitamin C, vitamin E, beta-carotene, coenzyme Q,OT-551, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, butylatedhydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), bilberryextract, and combinations thereof.
 23. The method according to claim 21,wherein the mineral is selected from the group consisting of cupricoxide, zinc oxide; selenium-containing compounds, and combinationsthereof.
 24. The method according to claim 21, wherein the negativelycharged phospholipid is selected from the group consisting ofcardiolipin, phosphatidylglycerol, and combinations thereof.
 25. Themethod according to claim 21, wherein the carotenoid is selected fromthe group consisting of zeaxanthin, lutein, and combinations thereof.26. The method according to claim 1 2, wherein the C₂₀-D₃-retinal,corresponding to the aldehyde of the C₂₀-D₃-retinol acetate,C₂₀-D₁₋₃-retinoid forms A2E in vitro about 7 times slower thannon-deuterium-enriched retinal the corresponding non-deuteratedretinoid.
 27. The method according to claim 1 2, wherein thepharmaceutical composition is administered directly to the eye.
 28. Amethod of treating a macular degeneration, comprising administering aneffective amount of a substituted C₂₀-D₁₋₃-retinoid to a patient in needthereof, wherein the substituted C₂₀-D₁₋₃-retinoid is selected from thegroup consisting of C₂₀-D₁₋₃-retinol, C₂₀-D₁₋₃-retinol ester,C₂₀-D₁₋₃-retinal and C₂₀-D₁₋₃-pro-vitamin A carotenoids.
 29. A method oftreating a macular degeneration, comprising administering an effectiveamount of a pharmaceutical composition to a patient in need thereof,wherein the pharmaceutical composition comprises a substitutedC₂₀-D₁₋₃-retinoid, wherein the C₂₀-D₁₋₃-retinoid is selected from thegroup consisting of C₂₀-D₁₋₃-retinol, C₂₀-D₁₋₃-retinol ester,C₂₀-D₁₋₃-retinal and C₂₀-D₁₋₃-pro-vitamin A carotenoids, and apharmaceutically acceptable carrier.
 30. The method according to claim29, wherein the substituted C₂₀-D₁₋₃-retinoid is a C₂₀-D₃-retinoid. 31.The method according to claim 29, wherein the pharmaceutical compositionis suitable for use as a nutraceutical composition.
 32. The methodaccording to claim 29, wherein the macular degeneration is age-relatedmacular degeneration.
 33. The method according to claim 32, wherein theC₂₀-D₁₋₃-retinoid is C₂₀-D₁₋₃-retinol or a C₂₀-D₁₋₃-retinol ester. 34.The method according to claim 32, wherein the C₂₀-D₁₋₃-retinoid isC₂₀-D₃-retinol, a C₂₀-D₃-retinol ester, C₂₀-D₃-retinal, or aC₂₀-D₃-pro-vitamin A carotenoid.
 35. The method according to claim 32,wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinol acetate.
 36. The methodaccording to claim 35, wherein the C₂₀-D₃-retinol acetate forms A2Eabout 7 times slower than non-deuterium-enriched retinol acetate. 37.The method according to claim 32, wherein the patient is in need oftreatment for dry (non-neovascular) age-related macular degeneration.38. The method according to claim 29, wherein the macular degenerationis Stargardt disease.
 39. The method according to claim 38, wherein theC₂₀-D₁₋₃-retinoid is C₂₀-D₁₋₃-retinol or a C₂₀-D₁₋₃-retinol ester. 40.The method according to claim 38, wherein the C₂₀-D₁₋₃-retinoid isC₂₀-D₃-retinol, a C₂₀-D₃-retinol ester, C₂₀-D₃-retinal, or aC₂₀-D₃-pro-vitamin A-carotenoid.
 41. The method according to claim 38,wherein the C₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinol acetate.
 42. The methodaccording to claim 41, wherein the C₂₀-D₃-retinol acetate forms A2Eabout 7 times slower than non-deuterium-enriched retinal acetate. 43.The method according to claim 29, wherein the macular degeneration isselected from the group consisting of Vitelliform or Best disease,Sorsby's fundus dystrophy, retinitis pigmentosa, and MalattiaLeventinese.
 44. The method according to claim 43, wherein theC₂₀-D₁₋₃-retinoid is C₂₀-D₃-retinol acetate.
 45. The method according toclaim 29, wherein the macular degeneration is characterized by one ormore mutation(s) in the ABCA4 gene.
 46. The method according to claim29, wherein the substituted C₂₀-D₁₋₃-retinoid is present in thepharmaceutical composition at a level sufficient to deliver on averageabout 0.1 to about 90 mg/day to a patient.
 47. The method according toclaim 29, further comprising an additional active.
 48. The methodaccording to claim 47, wherein the additional active is selected fromthe group consisting of eye antioxidants, minerals, negatively-chargedphospholipids, carotenoids, and combinations thereof.
 49. The methodaccording to claim 47, wherein the eye antioxidant is selected from thegroup consisting of vitamin C, vitamin E, beta-carotene, coenzyme Q,OT-551, 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, butylatedhydroxytoluene, resveratrol, a trolox analogue (PNU-83836-E), bilberryextract, and combinations thereof.
 50. The method according to claim 47,wherein the mineral is selected from the group consisting of cupricoxide, zinc oxide, selenium-containing compounds, and combinationsthereof.
 51. The method according to claim 47, wherein the negativelycharged phospholipid is selected from the group consisting ofcardiolipin, phosphatidylglycerol, and combinations thereof.
 52. Themethod according to claim 47, wherein the carotenoid is selected fromthe group consisting of zeaxanthin, lutein, and combinations thereof.53. The method according to claim 29, wherein the C₂₀-D₁₋₃-retinoidforms A2E about 7 times slower than non-deuterium enriched retinoid. 54.The method according to claim 29, wherein the pharmaceutical compositionis administered directly to the eye.